Project 2 - Imaging of Brain Connrectivity, Structure and Function

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Project 2 – Project Summary / Abstract Alzheimer’s disease (AD) is the most common cause of cognitive impairment in older adults and affects over 5.8 million people in the US alone. Individuals who carry the apolipoprotein E-ε4 (APOE4) gene are at heightened risk for developing late onset AD. Project 2 of the proposed P01 renewal “Vascular Contributions to Dementia and Genetic Risk Factors for Alzheimer’s Disease” will provide critical advances towards discovering how changes in brain connectivity, structure and function relate to neurovascular and blood-brain barrier (BBB) integrity and ultimately confer cognitive impairment in APOE4 carriers (e3/e4, e4/e4) relative to APOE3 homozygotes (e3/e3). Project 2 will follow 402 APOE4 carriers and 465 APOE3 homozygotes, initially enrolled as CU (75%) and MCI (25%) at baseline, who will continue to be evaluated longitudinally for changes in brain connectivity in relation to neurovascular and cognitive function. Participants will continue to receive the same imaging protocol to enable longitudinal analyses, including 1) multi-shell DTI for white matter connectivity; 2) resting fMRI for functional connectivity; 3) structural MRI for gray matter shape, volume; and 4) DCE-MRI for BBB integrity (Project 1), as well as BBB/neurovascular unit (NVU) biofluid biomarkers (Core B). For preclinical AD staging, we will follow the AT(N) biomarkers framework. For cognitive assessment, we will use the UDS 3.0 cognitive tests and supplemental tests across different cognitive domains to evaluate the relationships between neurovascular/BBB dysfunction and biomarkers, structural and functional connectivity, and cognitive function following the AT(N) research framework. Participants will also complete amyloid and tau PET scans to examine the effect of amyloid and tau on brain function and structure in a prespecified analysis. The role of neurovascular integrity and brain connectivity in the pathophysiology of preclinical cognitive decline and clinical progression to mild cognitive impairment (MCI) and AD have only begun to be elucidated. Using advanced neuroimaging methodology, this project will apply a hypothesis-driven approach to understand how impairment in the BBB impact brain structure and function and cognition in APOE4 carriers relative to APOE3 homozygotes.